Acetylcholine is a major neurotransmitter in the brain and peripheral nervous systems; it induces a variety of physiological and behavioral responses by binding and activating specific receptors that belong to the muscarinic (defined on the basis of their activation by muscarine) and nicotinic (defined on the basis of their activation by nicotine) acetylcholine receptor families.
Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a family of ligand-gated ion channels that are distributed extensively throughout the central and peripheral nervous systems. The nAChRs are the main mediators of fast synaptic transmission in ganglia, and therefore, are key molecules for the processing of neural information in the autonomic nervous system. The nAChRs are involved in the control of organ systems such as heart, gut, and bladder. In this respect, it is important to note that ulcerative colitis (UC) is a disease largely of non-smokers, in which nicotine is of therapeutic value. The mode of action is unknown, but may involve nicotinic acetylcholine receptors (nAChRs) in the bowel wall (Richardson, C. E., J. M. Morgan, et al. (2003). “Effect of smoking and transdermal nicotine on colonic nicotinic acetylcholine receptors in ulcerative colitis.” Q J Med 96: 57-65).
In the brain, beyond their role in relation to tobacco use, nAChRs are involved in a wide variety of behavioral functions including cognitive function (Araki, H., K. Suemaru, et al. (2002). “Neuronal Nicotinic Receptor and Psychiatric Disorders: Functional and Behavioral Effects of Nicotine.” Jpn. J Pharmacol 88: 133-138). Both acute and chronic nicotine administration significantly improves working memory performance of rats in the radial-arm maze. In humans, activation of nAChRs provides beneficial treatment for cognitive dysfunction such as Alzheimer's disease (AD), schizophrenia, and attention deficit hyperactivity disorder (ADHD). Nicotine has been shown to improve attentional performance in all of these disorders. The nAChRs participate in the pathogenesis of several brain disorders (Parkinson's and Alzheimer's diseases, Tourette's syndrome, schizophrenia, depression, attention deficit disorder). In the same diseases, clinical studies showed that nicotine had beneficial effects, both as a therapeutic and prophylactic agent.
Activation of neuronal nicotinic acetylcholine receptors (nAChRs) has been shown to maintain cognitive function following aging or the development of dementia (Picciotto, M. R. and M. Zoli (2002). “Nicotinic Receptors in Aging and Dementia.” J Neurobiol 53(4): 641-55). Nicotine and nicotinic agonists have been shown to improve cognitive function in aged or impaired subjects (Rezvani, A. H. and E. D. Levin (2001). “Cognitive Effects of Nicotine.” Biol Psychiatry 49: 258-267). Smoking has also been shown in some epidemiological studies to be protective against the development of neurodegenerative diseases. This is supported by animal studies that have shown nicotine to be neuroprotective both in vivo and in vitro. Treatment with nicotinic agonists may therefore be useful in both slowing the progression of neurodegenerative illnesses, and improving function in patients with the disease. Nicotine addiction (primarily through tobacco smoking) is a chronic relapsing condition that can be difficult to treat. DSM-IV (Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition, published by the American Psychiatric Association, Washington D.C., 1994) has included a nicotine withdrawal syndrome that is characterized by craving for cigarettes, irritability, anxiety, inner tension, and concentration difficulties. These symptoms are usually observed within the first two weeks after sudden cessation of smoking although some can be experienced as early as 4-6 h after the last cigarette. Nicotine replacement therapy attenuates these symptoms.
Nicotinic acetylcholine receptor pharmacology is becoming increasingly important in the clinical symptomatology of smoking cessation and neurodegenerative diseases in general, and of cognitive and behavioral aspects in particular. Cholinesterase inhibitors (ChEIs) inhibit the degradation of acetylcholine thereby increasing its concentration in the brain. ChEIs are used for the treatment of dementia, by virtue of their ability to increase brain acetylcholine concentrations that subsequently cause activation of nAChRs.
In addition, the concept of allosteric modulation of nicotinic acetylcholine receptors has become a research focus for the development of therapeutic agents. Within this context, galantamine, a recently approved drug for cognition enhancement in Alzheimer's disease, modestly inhibits acetylcholinesterase and has an allosteric potentiating ligand effect at nicotinic receptors (Woodruff-Pak, D. S., C. Lander, et al. (2002). “Nicotinic Cholinergic Modulation: Galantamine as a Prototype.” CNS Drug Reviews 8(4): 405-426). Other examples of such acetylcholinesterase inhibitors include, but are not limited to piperidines such as donepezil, and carbamates such as rivastigmine.
Of major interest, however, is the fact that the activity of the different subtypes of neuronal nAChR is also subject to modulation by substances of endogenous origin such as choline, the tryptophan metabolite kynurenic acid, neurosteroids, and beta-amyloid peptides, and by exogenous psychotomimetic drugs such as phencyclidine and ketamine (Pereira, E. F., C. Hilmas, et al. (2002). “Unconventional Ligands and Modulators of Nicotinic Receptors.” J Neurobiol 53(4): 479-500). Recently, sustained-release bupropion (bupropion SR) treatment was found efficacious in smoking cessation (Jorenby, D. (2002). “Clinical Efficacy of Bupropion in the Management of Smoking Cessation.” Drugs 62(2): 25-35).
While nicotinic cholinergic receptors are present in many brain regions, it remains unclear which are important for the effects of nicotine on sleep and daytime alertness, although it is clear that such effects are present. There is also little literature on the effects of nicotine on sleep in non-smokers, while early nicotine withdrawal has been associated with sleep fragmentation in smokers (Wetter, D. W., M. C. Diore, et al. (1995). “Tobacco Withdrawal and Nicotine Replacement Influence Objective Measures of Sleep.” Journal of Consulting and Clinical Psychology 63(4): 658-667).
One of the significant observed side effects of patch nicotine replacement is insomnia (Jorenby, D. E., S. J. Leischow, et al. (1999). “A Controlled Trial of Sustained-Release Bupropion, A Nicotine Patch, or Both for Smoking Cessation.” The New England Journal of Medicine 340(9): 685-691). Based on the known stimulating effects of nicotine on cortisol secretion, markedly reduced cortisol concentrations are likely to be a neuroendocrine consequence of abstinence from smoking. Nicotine replacement therapy may activate the HPA axis and increase cortisol levels. Such activation may presumably lead to sleep problems as recent findings suggest that high cortisol levels are associated with poor sleep quality (Rodenbeck, A., G. Huether, et al. (2002). “Interactions between evening and nocturnal cortisol secretion and sleep parameters in patients with severe chronic primary insomnia.” Neuroscience Letters 324: 159-163; and Vgontzas, A. N., E. O. Bixler, et al. (2001). “Chronic Insomnia Is Associated with Nyctohemeral Activation of the Hypothalamic-Pituitary-Adrenal Axis: Clinical Implications.” J Clin Endocrinol Metab 86(8): 3787-3794).
Melatonin, the hormone secreted at night by the pineal gland, has sleep promoting properties when given at daytime, namely when its levels in the body are low. The effect observed, shortening of sleep latency, is regarded as evidence of hypnotic activity of a drug (benzodiazepines and non-benzodiazepines), though hypnotic drugs usually impair daytime vigilance. Indeed, melatonin, like hypnotic drugs, produces a significant decrease in vigilance and performance during the first hours after its administration (Wurtman U.S. Pat. No. 5,641,801 Jun. 24, 1997; Graw, P., E. Werth, et al. (2001). “Early morning melatonin administration impairs psychomotor vigilance.” Behavioural Brain Research 121: 167-172; Dollins, A. B., H. J. Lynch, et al. (1993). “Effect of pharmacological daytime doses of melatonin on human mood and performance.” Psychopharmacology 112: 490-496).
Moreover, an expert in the field may report that melatonin in fact harms vigilance, as indeed has been found in depressed patients following one week of daily administration of oral melatonin (Sherer, M. A., H. Weingartner, et al. (1985). “Effects of melatonin on performance testing in patients with seasonal affective disorder.” Neuroscience Letters 58: 277-82). Therefore, at low doses (0.3-10 mg), melatonin's pharmacological activity is regarded as hypnotic. As such, it is not expected to improve psychomotor or cognitive performance shortly after its administration, or improve daytime functioning.
The sleep inducing effects of melatonin at night have been demonstrated in elderly patients with insomnia, in whom melatonin production is low due to aging and diseases, and additional cases in which melatonin deficiency was apparently involved. Administration of melatonin at night (0.3-2 mg daily for 1-3 weeks) improves sleep compared to placebo in elderly subjects with insomnia (Haimov, I., P. Lavie, et al. (1995). “Melatonin replacement therapy of elderly insomniacs.” Sleep 18(7): 598-603; 18:598-603; Garfinkel, D., M. Laudon, et al. (1995). “Improvement of sleep quality in elderly people by controlled-release melatonin.” The Lancet 346: 541-544). However, melatonin may be less effective at night in younger patients with insomnia who apparently produce sufficient amounts of melatonin endogenously (James, S. P., D. A. Sack, et al. (1990). “Melatonin administration in insomnia.” Neuropsychopharmacology 3: 19-23; James, S. P., W. B. Mendelson, et al. (1987). “The effect of melatonin on normal sleep.” Neuropsychopharmacology 1: 41-44). In a recent study melatonin (0.5 mg) was administered as immediate-release (evening or mid-night administration) or prolonged-release forms (evening administration) to a group of patients with age-related sleep maintenance insomnia. All three melatonin treatments shortened latencies to persistent sleep but were not effective in sustaining sleep (Hughes, R. J., R. Sack, et al. (1998). “The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement.” Sleep 21(1): 52-68). Therefore, melatonin may not be effective in promoting sleep at night in patients who produce sufficient amounts of the hormone endogenously.
Studies in vivo have failed to demonstrate significant effects of nicotine on the endogenous melatonin production in animals and humans (Tarquini, B., F. Perfetto, et al. (1994). “Daytime circulating melatonin levels in smokers.” Tumori 80: 229-232; Gaddnas, H., K. Pietila, et al. (2002). “Pineal melatonin and brain transmitter monoamines in CBA mice during chronic oral nicotine administration.” Brain Research 957: 76-83). Thus, it could not have been inferred that melatonin might alleviate sleep problems associated with nicotine treatment, either in the form of cigarette smoking or upon nicotine replacement therapy for smoking cessation. In one study, administration of exogenous melatonin alone without nicotine replacement therapy, shortly after smoking cessation (4 hours), alleviated symptoms of acute nicotine withdrawal, compared to placebo treated control subjects; administration of melatonin (4 mg, i.p.) was not associated with an increase of a feeling of sedation or fatigue in these subjects (Zhdanova, I. and V. Piotrovskaya (2000). “Melatonin treatment attenuates symptoms of acute nicotine withdrawal in humans.” Pharmacology, Biochemistry and Behavior 67: 131-135). These data suggest that melatonin alone may alleviate symptoms of smoking cessation, but would not suggest that at the same time it would also be able to alleviate symptoms of nicotine replacement therapy. Since on the one hand, nicotine does not suppress melatonin production, and on the other hand melatonin may not be effective in improving sleep in subjects who produce sufficient amounts of the hormone, and, in addition, any hypnotic activity of melatonin is expected to be associated with a deterioration in cognition and performance, nothing in the available data suggest that melatonin might be a useful agent in alleviating the insomnia incurred by nicotine replacement therapy or that it would enhance the cognitive effects of nicotine.
In Markus, R. P., J. M. Santos, et al. (2003). “Melatonin Nocturnal Surge Modulates Nicotinic Receptors and Nicotine-Induced [3H]-Glutamate Release in Rat Cerebellum Slices.” JPET Fast Forward. 45625, it is reported that the [(3)H]-glutamate overflow induced by alpha7 nAChRs activation was higher during the dark phase (when melatonin is produced endogenously) and that the nocturnal increase in nicotine-evoked [(3)H]-glutamate release is imposed by a nocturnal surge of melatonin, as it is abolished when pineal melatonin production is inhibited by either maintaining the animals in constant light for 48 hours or by injecting propranolol just before lights off for two days; it is concluded that nicotine-evoked [(3)H]-glutamate release in rat cerebellum presents a diurnal variation, driven by the endogenous nocturnal pineal melatonin surge.
Markus, R. P. M., A, W. M. Zago, et al. (1996). “Melatonin modulation of presynaptic nicotinic acetylcholine receptors in the rat vas deferens.” The Journal of Pharmacology and Experimental Therapeutics 279: 18-22, reported higher sensitivity to nicotine in prostatic portions incubated with exogenous melatonin, and in organs from animals killed at night, after the rise of endogenous melatonin, and concluded that this is probably due to the appearance of low-affinity neuronal nicotinic ACh binding sites.
The Markus articles appear to imply that melatonin enhances the effects of nicotine. If extrapolated to humans, the Markus results could explain the beneficial effects of melatonin during smoking cessation, in absence of exogenous nicotine administration, as demonstrated by Zhdanova. However, they would also imply that melatonin would exacerbate the nicotine-induced insomnia in smoking cessation, in subjects treated with nicotine.
Oral delivery of nicotine for therapeutic purposes has been proposed, e.g. in U.S. Pat. No. 6,183,775 (see below), as well as in WO8803803, WO02076211 and published US Patent Application 2001029959.
Published US Patent Applications 20030051728 and 20030062042 disclose methods of delivering a physiologically active compound (e.g. nicotine and melatonin among many others) as an aerosol.
U.S. Pat. No. 6,183,775 discloses a controlled release lozenge comprising active substances, among which are mentioned nicotine and melatonin.
U.S. Pat. No. 6,068,853 describes a transdermal delivery device for delivery of active agents, and mentions types, as well as specific instances, of active agents, e.g. melatonin and nicotine.
U.S. Pat. No. 5,284,660 describes a device which delivers drugs to the skin or to the mucosa at predetermined intervals. The deliverable drugs may be e.g., nicotine (for daytime administration) or melatonin (for night-time administration). Neither this patent, nor any other of the patent documents (patents and published patent applications) mentioned herein, describe or suggest combined administration of nicotine and melatonin.
The entire contents of the patent documents (patents and published patent applications) mentioned herein are incorporated by reference in the present patent application.
It has now surprisingly been found, in relation to nicotine treatment, that exogenous melatonin produces a significantly greater benefit in insomnia patients who are habitual smokers compared to non-smokers. The synergistic effect of nicotine and melatonin on sleep has not been observed before, and is of potential utility in clinical interventions that involve nAChRs activation or particularly nicotine administration, to alleviate sleep problems incurred by these treatments. Besides, concomitant treatment by melatonin and nicotinic acetylcholine receptor modulation offers potentially significant benefits over nicotinic activation alone, in improving cognitive function in the elderly in general and in Alzheimer's disease patients in particular. Since sleep is important for memory consolidation (Maquet, P. (2001). “The Role of Sleep in Learning and Memory.” Science 294: 1048-1052), concomitant melatonin-nicotinic therapy might also be expected to improve next day cognitive and memory functions due to enhanced sleep-dependent memory consolidation.